Prevalence and severity of disease varies geographically in a wide array of mammals and birds that protozoan pathogens infect. To reduce the burden of emerging parasitic disease among prevalent zoonoses, a primary goal of our work is to discover the transmission dynamics and the phylogenetic relationships among circulating protozoan parasites that possess complex life cycles and multiple routes of transmission in nature. We seek discoveries in these areas to support the development of new diagnostic tools, identify fundamental paradigms governing virulence shifts in parasitic protozoa and develop efficacious anti-protozoal strategies that mitigate the spread of disease. Periodic shifts in the population genetics and transmission dynamics of pathogenic clones of coccidian parasites such as Toxoplasma gondii and Sarcocystis neurona have been of substantial interest to the parasitology community because both of these heterogamous pathogens possess surprisingly clonal population genetic structures that are punctuated by the dominance of only a few highly successful clones. The genetic basis for how these clones emerge and then rapidly come to dominate has been a matter of intensive study, and great debate. We previously showed that protozoan parasites functionally clone themselves via self-mating during their sexual cycle in nature and this exists as an important factor governing the emergence and/or expansion of clones that can sweep to dominance, or cause virulent epidemics. These data served as the first extensive from-the-field evidence that self-mating is a key adaptation allowing expansion of parasite clones capable of causing disease epidemics. We have recently expanded our analyses beyond the coccidia to determine the extent to which sexual reproduction is impacting the population genetics for a wide range of human-infective protozoan parasites, including stremenopiles (e.g., blastocystis), diplomonads (e.g., Giardia intestinalis), kinetoplastids (e.g., Leishmania spp. and Trypanosoma spp.) and the coccidia (e.g., Toxoplasma, Neospora, Sarcocystis). Our recent work examining patients who experience Ocular Toxoplasmosis (OT) has identified a subset of strains that gain access to the eye and cause serious disease. OT affects 1/400 people globally, and can cause serious vision loss or blindness, but the genetic factors governing disease are largely unresolved. We addressed whether parasite genetic type predicts disease and we developed an ELISA-based blood test to detect the presence of strain-specific antibodies circulating among seropositive individuals with OT versus those without OT. Using this test, we discovered a novel serotype that identified acutely infected patients who were six times more likely to develop OT. Furthermore, this NR serotype was associated with larger lesions and recurrent disease and the strains responsible for these infections were not Type II, the most common strain infecting people. This work demonstrated that Toxoplasma parasite strain type is a significant factor influencing human disease and supports the value of screening for toxoplasmosis to identify susceptible patients who might benefit from prophylactic intervention to reduce disease.